Research in a Nugget

Brief description of research

Investigation of Enzymatic and Non-enzymatic Reaction Mechanisms Computational chemistry is a fast emerging field and today is widely applied to solve complex chemical and biochemical problems in both academia and the chemical and pharmaceutical industries. In this field, highly accurate quantum chemical methods implemented in the advanced commercial software and state-of-the-art computers including supercomputing facilities are used to explore chemistry. In our research group, we apply computational approaches, namely pure quantum mechanical (QM), hybrid quantum mechanics/ molecular mechanics (QM/MM) and molecular simulations, to investigate reaction mechanisms catalyzed by both enzymatic and non-enzymatic systems.

Computational study of Alzheimer's disease Beta-amyloidosis and oxidative stress have been implicated as root causes of Alzheimer’s disease (AD). Beta-amyloidosis could be described as the generation and extracellular aggregation of 40-42 amino acid residues containing amyloid beta (Aß) peptides to form senile plaques. The Aß42 peptide has been observed to be a major component of these plaques. According to a widely accepted theory concerning the role of these peptides in AD known as the oxidative stress mechanism, the aggregated Aß peptide, in concert with oxidants and bound metal ions (Cu(II), Zn(II) and Fe(III)), initiates free radical processes resulting in the formation of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide and hydroxyl radicals, which eventually leads to neuronal death. The current potential therapeutic strategies for AD include blocking the generation and aggregation of Aß peptides, inhibiting the cytotoxic effects, and disrupting of preformed fibrils. However, our efforts in this direction are hindered by the lack of atomic level understanding of biochemical processes occurring in AD. Due to inherent complexities (absence of x-ray structures, fast rate of aggregation, insolubility of aggregates, short life-time and intricate electronic structure of intermediates, etc.) this understanding can’t be achieved by experiments alone and requires multidisciplinary scientific approaches. We propose a radically different approach to this problem through the development and application of a comprehensive theoretical and computational strategy involving molecular dynamics (MD), quantum mechanics (QM), hybrid quantum mechanics/molecular mechanics (QM/MM), bioinformatics and spectroscopy techniques to investigate complex chemical and physical processes in beta-amyloidosis and the oxidative stress mechanism. In particular, we aim to study generation, degradation, and prevention of the aggregation of Aß-peptides, and disruption of preformed Aß-fibrils. The outcome of our studies will provide an atomic level understanding of biochemical processes occurring in AD and their outcome will advance our efforts to develop effective therapeutic strategies for this disease.

A DFT Study of the Mechanism of Ni Superoxide Dismutase (NiSOD): Role of the Active Site Cysteine-6 Residue in the Oxidative Half-Reaction Rajeev Prabhakar, K. Morokuma, and D. G. Musaev Journal of Computational Chemistry 2006, 27:1438-1445.

A DFT study of the Mechanism for the biogenesis of cofactor topaquinone (TPQ) in Copper Amine Oxidases (CAOs) Rajeev Prabhakar and Per E.M. Siegbahn Journal of American Chemical Society2004, 107(16); 3944 -3953.